Through studies proposed here, we will develop a strategy for antigen-specific negative immunization to prevent and treat contact dermatitis. Further, the studies proposed will establish a model approach that could be extended for the development of therapies to prevent or treat a broad range of T-cell mediated inflammatory skin diseases. We propose to manipulate neuroinflammatory responses in the skin at the moment of antigen challenge to prevent the development of antigen-specific T-cell responses including prevention of the development of T-cell memory. Further, we will extend this strategy to mitigate/abrogate established memory T-cell responses that underlie chronic inflammatory skin diseases. To accomplish this we will utilize novel microneedle array (MNA) technology developed in our laboratory. These MNAs have been formulated to achieve simultaneous delivery of antigen (Ag) and neuroimmunomodulatory small molecules to a specific skin stratus. By combining this innovative immune-regulatory approach with our novel MNA delivery technology, we will engineer the cutaneous microenvironment in vivo. The purpose of our approach is to generate Ag specific anti-inflammatory antigen presenting cells (APCs) capable of presenting Ag to T cells in a tolerogenic fashion. This strategy will enable, for the first time an Ag-specific therapy for the prevention and treatment of T-cell mediated skin diseases. We will evaluate the effects of this strategy on the prevention of Ag-specific effector and memory T-cells (Aim 1), and the mitigation/abrogation of preexisting memory responses (Aim 2). We will determine mechanisms that prevent immune induction, including effects on skin APC function, and memory T-cell induction, function, and survival. Importantly, our experiments include translational studies focusing on human skin (Aims 1 and 2) that are specifically designed to enable rapid translation of this strategy to clinical trials.